A Pt(IV)-based mononitro-naphthalimide conjugate with minimized side-effects targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance
A Pt(IV)-based mononitro-naphthalimide conjugate with minimized side-effects targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance
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基于 Pt(IV) 的单硝基萘酰亚胺缀合物，通过双 DNA 损伤方法将副作用降至最低，以 DNA 损伤响应为目标，克服顺铂耐药性。
DOI：
10.1016/j.bioorg.2020.104011
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发表时间：
2020-08-01
影响因子：
5.1
通讯作者：
Xie, Songqiang
中科院分区：
文献类型：
--
作者：
Li, Yingguang;Yue, Kexin;Xie, Songqiang
铂(Pt)(II)药物和新型Pt(IV)药物由于DNA损伤修复而导致细胞凋亡失调，因此在治疗耐药肿瘤时效果较差。据报道，单硝基萘酰亚胺 Pt(IV) 复合物 10b 具有最小的副作用，通过双 DNA 损伤方法靶向 DNA 损伤反应，以克服顺铂耐药性。与顺铂（52.88%）相比，10b显示出显着的体内抗肿瘤活性（70.10%）。 A549cisR 细胞的最高倍数增加 (FI) (5.08) 和 A549 的最低倍数增加 (0.72) 表明 10b 优先在耐药细胞系中积累。可能的分子机制表明10b以与现有Pt药物完全不同的方式靶向耐药细胞。 10b 的基因组 DNA 中的细胞积累和 Pt 水平几乎比顺铂和奥沙利铂高 5 倍，表明 10b 中的萘酰亚胺部分优先表现出 DNA 损伤。使用 5'-dGMP 作为 DNA 模型，在抗坏血酸 (5 mM) 存在下，10b (1 mM) 与 5'-dGMP (3 mM) 的 DNA 结合特性推断，10b 是由抗坏血酸还原后顺铂与 5'-dGMP 结合生成的。此外，10b比顺铂更有效地促进p53基因和蛋白质的表达，从而增强抗癌活性。上调的γ H2A.X和下调的RAD51表明10b不仅诱导严重的DNA损伤，而且抑制DNA损伤修复，从而导致其细胞毒性高于顺铂。与匹配的正常细胞（HL-7702 细胞）相比，它们在癌细胞（SMMC-7721）中优先积累，这表明它们对于临床治疗用途具有潜在的安全性。此外，4T1细胞的体内治疗指数高达10b，表明萘二甲酰亚胺-Pt(IV)缀合物在乳腺癌治疗中发挥着重要作用。我们的研究首次表明铂类药物在一个全新领域中通过双重 DNA 损伤机制来治疗耐药性癌症的重要策略，即通过双 DNA 损伤机制修复 DNA 损伤。
Platinum(Pt)(II) drugs and new Pt(IV) agents behave the dysregulation of apoptosis as the result of DNA damage repair and thus, are less effective in the treatment of resistant tumors. Herein, mononitro-naphthalimide Pt(IV) complex 10b with minimized side-effects was reported targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance. 10b displayed remarkably evaluated antitumor (70.10%) activities in vivo compared to that of cisplatin (52.88%). The highest fold increase (FI) (5.08) for A549cisR cells and the lowest (0.72) for A549 indicated 10b preferentially accumulated in resistant cell lines. The possible molecular mechanism indicates that 10b targets resistant cells in a totally different way from the existing Pt drugs. The cell accumulation and the Pt levels in genomic DNA from 10b is almost 5 folds higher than that of cisplatin and oxaliplatin, indicating the naphthalimide moiety in 10b exhibits preferentially DNA damage. Using 5 '-dGMP as a DNA model, the DNA-binding properties of 10b (1 mM) with 5 '-dGMP (3 mM) in the presence of ascorbic acid (5 mM) deduced that 10b was generated by the combination of cisplatin with 5 '-dGMP after reduction by ascorbic acid. Moreover, 10b promoted the expression of p53 gene and protein more effectively than cisplatin, leading to the increased anticancer activity. The up-regulated gamma H2A.X and down-regulated RAD51 indicates that 10b not only induced severe DNA damage but also inhibited the DNA damage repair, thus resulting in its higher cytotoxicity in comparison to that of cisplatin. Their preferential accumulation in cancer cells (SMMC-7721) compared to the matched normal cells (HL-7702 cells) demonstrated that they were potentially safe for clinical therapeutic use. In addition, the higher ther-apeutic indices of 10b for 4T1 cells in vivo indicated that naphthalimide-Pt(IV) conjugates behaved a vital function in the treatment of breast cancer. For the first time, our study implies a significant strategy for Pt drugs to treat resistance cancer targeting DNA damage repair via dual DNA damage mechanism in a totally new field.